The Flavonoids Daidzein and Genistein Induce Wall‐Deficient Cell Formation in Streptomyces coelicolor Under Hyperosmotic Stress

Streptomycetes exhibit a complex multicellular life cycle, including programmed cell death and hyphal differentiation, and can generate extracellular vesicles and wall-deficient cells such as S-cells and L-forms. These wall-deficient morphotypes are increasingly recognised as functional bacterial states with emerging biotechnological relevance, yet the environmental signals that trigger their formation remain poorly defined. Here, we show that the flavonoids daidzein and genistein act as defined chemical inducers of wall-deficient cell formation in Streptomyces coelicolor under hyperosmotic stress (0.64 M sucrose). Although the wild-type strain fails to produce wall-deficient cells in standard laboratory media under hyperosmotic conditions, robust formation of non-dividing stress-induced cells (S-cells), along with a small proportion of dividing L-forms, is observed in soya flour-mannitol medium (SFM) supplemented with high sucrose concentrations. We show that wall-deficient cell formation can be induced by the addition of daidzein and genistein, the most abundant soybean flavonoids, to flavonoid-free media containing high sucrose concentrations, at levels comparable to those found in SFM. These results identify flavonoids as defined chemical inducers of wall-deficient morphogenesis in Streptomyces. More broadly, our findings suggest a link between plant secondary metabolites and bacterial morphological plasticity, with potential implications for plant-microbe interactions and microbial biotechnology.